It is well established that rotavirus is the leading cause of severe diarrhoea among infants and young children. It is estimated that globally 0.5-0.6 million children under the age of 5 die annually due to rotavirus diarrhea and another 2 million are hospitalized. About 90% to 95% of these deaths occur mainly in developing countries.
Rotavirus is highly contagious and resistant regardless of water quality and available sanitation nearly every child in the world is at risk of infection. Vaccination has been proven to be the most effective means of prophylaxis for rotavirus infection. International research data suggests that current rotavirus vaccines have 85% to 95% efficacy against severe rotavirus gastroenteritis (RVGE). In light of this, the World Health Organization (WHO) on 5th Jun. 2009 recommended that rotavirus vaccine must be included in all the national immunization programs.
However, there are concerns while using the same in developing countries where 90% to 95% deaths occur due to rotavirus infection, and where access to treatment is also limited. The two major concerns faced by developing countries are 1) lower efficacy of rotavirus vaccines in developing and low resource countries and 2) programmatic suitability as well as cost of current available vaccines.
It has been reported that more than 2.4 million child deaths can be prevented by 2030 by accelerating access to rotavirus vaccines. If these vaccines are used in ‘Global Alliance for Vaccine and Immunization (GAVI)-countries, it could prevent an estimated 180,000 deaths and avert 6 million clinic or hospital visits each year, thereby saving US $68 million annually in the treatment cost.
However, in order to increase the reach of the rotavirus vaccines in these regions, new programmatically suitable vaccines must be developed and qualified for global use. Programmatic suitability is a new process developed by the WHO relating to the prequalification of vaccines with the aim to address needs of developing country and facilitating universal immunization without requiring additional investments in cold chain capacity, human resources, waste disposal facilities, etc. This process outlines Mandatory, Critical Unique, Innovative and Preferred programmatic suitability characteristics that a vaccine must possess for WHO prequalification.
It is well known in the art that the vaccines must be stored and transported at refrigerator temperature maintained in the range of 2° C. to 8° C. Further, it is also well known that vaccines must be administered immediately after being removed from refrigeration. Usually a WHO prequalified vaccine is stable for up to 24 to 36 months at 2° C. to 8° C.
The current WHO prequalified rotavirus vaccines are stable only for a limited duration at a particular temperature as mentioned above. Studies indicate that if the currently available vaccine, for example, Rotateq® vaccine is inadvertently exposed or stored at temperatures above 8° C., the potency is maintained for the maximum exposure of 48 hours (h) at 9° C. to 25° C. or for a bare 12 hours at 26° C. to 30° C. However, if RotaTeq® vaccine is exposed to temperatures above 30° C., or if the time mentioned above has lapsed, the vaccine has to be discarded since it has lost its potency. There is limited data to suggest that if the vaccine is inadvertently exposed to temperatures below 0° C., the potency of the vaccine is maintained. Another, currently available freeze dried vaccine i.e. Rotarix vaccine exhibit stability with a shelf life of 36 months at 2° C.-8° C.
However, irrespective of the stability profile both vaccines are required to maintain the cold chain during transport. It is very difficult to maintain the cold chain required to conserve the vaccine potency particularly in developing and low income countries resulting in large amount of vaccine being wasted and in worst case scenario endangering the lives of potential recipients. The WHO estimates that nearly half of freeze-dried and quarter of liquid vaccines are wasted each year. One of the biggest contributors to this wastage is disruption of the cold chain. The GAVI Alliance, which supports developing countries in their vaccination efforts, estimates that half of the healthcare facilities in the these countries have no electricity supply at all, with only 10% having a reliable electricity supply; an obligatory requirement for cold chain operation. For example, in India, a country which has largest burden of rotavirus disease, a National Cold Chain Assessment-2008 report by UNICEF in collaboration with Govt. of India, state governments and WHO, concluded that management of entire cold chain infrastructure and logistics suffers from acute shortage equipment, infrastructure and of trained manpower.
Thus there is a great demand for thermostable vaccines. Many existing vaccines do exhibit some degree of thermostability. However, the existing vaccines possess shorter period of thermostability (e.g. VVM 7 or VVM 14) which fails to address the issue and therefore, is difficult to reach to developing world. For example, in India, like most developing world, uses a multi-tier vaccine store network which receives, stores and supply huge quantity of vaccines with all vaccines requiring storage in a temperature range of +2° C. to +8° C. In this journey vaccines spend at least an year from manufacturer to recipients, putting huge burden on cold chain which is inadequate. Since cold chain is the most important component to ensure the quality of vaccine, developing a thermostable vaccine that could be transported and stored outside cold chain for extended period of time is on high priority for healthcare sector. This is particularly more important for freeze dried vaccine since it bears higher wastage burden.
The thermostability feature is also beneficial to vaccine logistics in regions of the world where ambient extremes of temperatures exceed 40° C. and where cold chain is not available nearby.
The presently available freeze dried vaccines does not possess enough thermostability profile suitable for storage outside cold chain for any meaningful amount of time and these have to be stored and transported under refrigeration. Hence there is a current lack of vaccines and the formulation processes that endow sufficient thermostability to a vaccine is therefore a significant barrier to global vaccination efforts, particularly for live attenuated vaccines. Understanding the possible mechanisms of destabilisation for the vaccine of interest and adjusting the vaccine formulation as well as tuning the process parameters is essential for quenching those mechanisms is essential for designing successful freeze drying process.
Although freeze drying confers extended stability on vaccine formulations, it incurs higher manufacturing costs. The cost of freeze drying is directly correlated to the scale which in turn is defined by surface area of the shelves. This can make thermostable freeze dried vaccine unattractive in terms of costs over its thermolabile liquid vaccine formulations. Thus there also arises a need for designing a cost-effective thermostabilization process.
Further, most of the existing solid forms of vaccines are packaged in separate containers/components and require syringe and a vial as well as other complex and costly mechanisms for reconstitution and administration. This causes difficulty in the administration of vaccine and also greatly increases the footprint of the vaccine by overburdening the cold chain. This also in turn increases the shipping and distribution challenges, logistics for storage and is prone to potentially fatal reconstitution errors like buffer/vaccine mismatch, contamination, administration of wrong volumes etc. Thus there is a need for innovative form of vaccine that offers flexibility in its filling in the improved containers/closures that improves logistics as well as administration of the vaccine.
The U.S. Pat. No. 6,616,931 (WO2002/011540) describes rotavirus vaccine stability in formulations differing in buffers, divalent metal ions, sugar and polyanions, surfactants, amino acids in both liquid and freeze dried forms. These formulations however failed to yield thermostability above 22° C. to 30° C. for any significant amount of time. It is also quoted that freeze drying of rotavirus vaccines can result in loss of viral titer which in turn result in low yields, and the potency below required levels resulting ineffective immunization by the freeze dried vaccine formulation. A reconstitution buffer is also reported for freeze dried formulations which provides additional acid-neutralizing capacity needed for buffering of gastric acid. This patent also discloses that incubation for 30 minutes at 37° C. or 2 hours at 30° C. of the reconstituted freeze dried formulation is subject to losing potency at room temperatures.
GlaxoSmithkline's U.S. Pat. No. 7,285,280 discloses a live attenuated rotavirus vaccine formulation. The vaccine formulation is freeze dried with Calcium Carbonate present as the antacid to be reconstituted with aqueous solution prior to administration. Alternatively, this patent also claim a vaccine formulation as a quick dissolving tablet in freeze dried form to be directly placed on the tongue of an infant/ child wherein the rotavirus antigen. Another GSK's U.S. Pat. No. 8,192,747 claims a liquid oral rotavirus formulation comprising live attenuated rotavirus antigen, a sugar a carboxylate and a carboxylic acid, adipic acid along with calcium ions, wherein the composition has an antacid capacity of at least 12 minutes.
The U.S. patent application 2012/0107356 describes vaccine formulation prepared without stabilizer with enhanced viral titers, shelf life and the thermostability. The shelf life can be further extended with addition of stabilizers. In spite of this remarkable thermostability the current licensed vaccine is a liquid form that requires storage at −20° C. Furthermore, the ingredients include proteins which, even if produced using processes supporting high yields, have a cost implications for formulations. For a vaccine to be broadly adopted in low income regions it is crucial to keep the cost of vaccine and its components such as stabilizers low. It is also crucial from the regulatory and safety point of view that excipient's and stabilizers used should contain neither substances of animal origin nor contain animal component. Indeed in some countries, it is not desirable for cultural and religious reasons as well.
International patent application no. PCT/US2008/011169 discloses freeze drying of the rotavirus formulations for preservation of rotavirus by using divalent cations as stabilizers such as Zn2+ and Ca2+ in liquid Rotavirus formulations. These fortified formulations demonstrated superior stability as is evidenced by the fact that the freeze drying did not cause instability to the vaccine. Using live G1 rotavirus strain as a representative serotype, freeze drying was carried out with different formulation compositions. Process loss for freeze drying was negligible to less than 0.2 log ffu/mL and the decrease in the initial titer was negligible to 0.7 log ffu/mL respectively after 2 months of storage at 37° C. The titer decrease was negligible after 3 months of storage at 4° C. and at 25° C. (<0.1 log ffu/mL).
One of the remarkable observation in the International patent application no. PCT/US2008/011169 was that the presence of Zn2+ in liquid rotavirus vaccines enhances the stability of virus viability, but in the U.S. Pat. No. 6,616, the presence of Zn2+ accelerated inactivation of rotavirus serotypes constituting RotaTeq. This observation however was not attributed to presence of divalent cations solely but to the concomitant presence of sucrose and pH.
For freeze drying, only conclusion drawn here was that presence of Zn2+ did not destabilize the rotavirus, either during the freeze drying process or during its storage at an elevated temperature. Thus the role of divalent cations for stabilization of rotavirus vaccine is not clear. It is also not clear that conclusions and claims based on experiments on single rotavirus serotype would be applicable to all rotavirus serotypes especially those constituting a multivalent rotavirus vaccine. Thus there is a need for rational design of formulation for arriving at an optimal and effective formulation(s).
Therefore, to cater to the abovementioned problems there is a need of a mono-dose, thermostable, cost effective vaccine which will be a great advantage to the vaccination program of developing and low income countries.
Thus, the present invention describes a thermostable vaccine with higher titre value and that could be transported in non-refrigerated supply chain significantly reducing the cost and complications associated with transporting vaccine to remote corners of the world.